A novel mechanism for oral controlled release of drugs by continuous degradation of a phospholipid prodrug along the intestine: In-vivo and in-vitro evaluation of an indomethacin–lecithin conjugate Arik Dahan a , Revital Duvdevani b , Eran Dvir b , Anat Elmann b , Amnon Hoffman a, ⁎ a Department of Pharmaceutics, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel b D-Pharm LTD, Rehovot, Israel Received 14 June 2006; accepted 5 December 2006 Available online 1 February 2007 Abstract Purpose: To investigate a novel mechanism for oral controlled release of drugs involving a continuous degradation of a phospholipid prodrug along the intestine. An indomethacin–lecithin conjugate with the drug attached to the sn-2 position of the phospholipid through a 5-carbon linker (DP-155) was used as a model molecule. Methods: The pharmacokinetics of DP-155 and free indomethacin liberated from the prodrug following intravenous, oral or intra-colon administration was investigated in rats, and evaluated in comparison to free indomethacin administration. Degradation by phospholipase A 2 (PLA 2 ) enzymes was assessed in-vitro. The impact of the linker length was evaluated in comparison to an indomethacin–phospholipid conjugate with a shorter linker (2-carbons). Results: Following oral or intra-colon DP-155 administration, free indomethacin was liberated along the intestine and absorbed into the systemic circulation, resulting in a controlled release profile of indomethacin in the plasma. The shorter linker caused a 20-fold decrease in the subsequent indomethacin absorption. DP-155 in-vitro degradation by PLA 2 was over 60%, while shorter linkers were profoundly less degradable. Conclusions: DP-155 caused a continuous input of free indomethacin into the plasma following degradation by PLA 2 in the gut lumen. Since the rate of drug release is not formulation dependent, the prodrug can be compounded even in a liquid dosage form. The phospholipid–drug conjugate is thus a potential novel mechanism for oral controlled release of drugs. © 2007 Elsevier B.V. All rights reserved. Keywords: Phospholipid–drug conjugate; Oral prodrug; Indomethacin; Controlled release; Pharmacokinetics; Phospholipase A 2 1. Introduction Oral controlled release formulations provide a variety of pharmacokinetic and pharmacodynamic advantages [1]. Most of the available techniques to control the rate of drug release within the gastrointestinal tract (GIT) are formulation dependent and are based on the dissolution or diffusion rate of the drug from the dosage form [2]. There are only a limited number of methods where the rate of drug release is governed by endogenous enzymes in the intestine, such as colonic drug delivery systems that are based on degradation of a prodrug by microorganisms of the colon flora [3,4] and colonic enzymes [5,6]. The current investigation proposes a conjugate of an active compound that releases the drug moiety along the GIT due to degradation by endogenous phospholipase enzymes. Hence, the controlled release profile is not governed by the dosage form or any additional excipients, and may be achieved even when a liquid dosage form is used. The prodrug approach, in which a derivative of the active compound is synthesized, has been proven to be an effective and important way of overcoming various ADME barriers that restrict the application of many chemical entities as orally administered drugs [7,8]. Journal of Controlled Release 119 (2007) 86 – 93 www.elsevier.com/locate/jconrel ⁎ Corresponding author. Department of Pharmaceutics, School of Pharmacy, The Hebrew University of Jerusalem, P. O. Box 12065, Jerusalem 91120, Israel. Tel.: +972 2 6757014; fax: +972 2 6757246. E-mail address: ahoffman@cc.huji.ac.il (A. Hoffman). 0168-3659/$ - see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.jconrel.2006.12.032